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EPIGENETIC REGULATION OF NON CpG ISLAND GENE PROMOTERS
by
Connie C. Cortez
_____________________________________________________________________
A Dissertation Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(BIOCHEMISTRY AND MOLECULAR BIOLOGY)
December 2008
Copyright 2008 Connie C. Cortez

DNA methylation and post-translational modifications of histones can specify transcriptional competency in both normal and cancer cells. However these epigenetic processes have largely been studied in the context of genes that contain CpG islands in their promoters. Therefore the epigenetic regulation of genes without CpG islands was explored in order to understand how epigenetics controls the expression of the remainder of the genome and provide insight into what aberrancies occur at these regions during cancer. Additionally, because there is an ongoing quest to find drugs that target the aberrancies that occur in the epigenome during cancer, methyltransferase inhibitors were also studied to test their potential as an epigenetic therapeutic.; Two genes, RUNX3 and LAMB3, were studied because they both contain non CpG island promoters. However, RUNX3 has two contrasting promoters: a non CpG island promoter that was found to have a cell type specific DNA methylation pattern and a second CpG rich promoter that was found to have a cancer specific DNA methylation pattern in bladder cancer. LAMB3 also displayed a tissue specific methylation and expression pattern in normal tissues. Interestingly, the non CpG island promoters of RUNX3 and LAMB3 could be induced in bladder cancer cell lines by the inhibition of DNA methylation with 5-Aza-2'-deoxycytidine, supporting the role DNA methylation has in their transcriptional control, regardless of CpG density. Additionally, chromatin immunoprecipitation performed at the non CpG island promoters of both genes demonstrated that DNA methylation and histone modifications together can regulate RUNX3 and LAMB3. Taken together, these data demonstrate the type of control epigenetic mechanisms have in the regulation of non CpG island promoters.; The histone methylation transferase inhibitor, 3-deazaneplanocin, was investigated to better understand its effects on cancer cells and was shown to be able to inhibit many types of histone methylation marks. Treatment of cancer cells with 3-deazaneplanocin was able to induce expression from the non CpG island promoters of LAMB3 and KRT7 as well as many genes that could not be induced by 5-Aza-2'-deoxycytidine, suggesting a combination treatment of these two types of drugs may be promising in cancer treatment.

EPIGENETIC REGULATION OF NON CpG ISLAND GENE PROMOTERS
by
Connie C. Cortez
_____________________________________________________________________
A Dissertation Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(BIOCHEMISTRY AND MOLECULAR BIOLOGY)
December 2008
Copyright 2008 Connie C. Cortez